1. Field of the Invention
This invention relates to bis-(N,Nxe2x80x2-bis-(2-haloethyl)amino)phosphoramidates, pharmaceutical compositions containing them, methods of treatment using them, and processes for their preparation. The compounds possess anti-tumor activities or are capable of being modified to have anti-tumor activities; and this invention relates to the use of the compounds in methods for the treatment of tumors and, especially, for the treatment of cancer.
2. Description of Related Art
Current cancer chemotherapy protocols involve administration to patients of anti-mitotic drugs such as adriamycin, vincristine, cisplatin, doxorubicin, daunomycin and methotrexate, toxins such as diphtheria toxin, pseudomonas toxin and ricin, and anti-tumor drugs such as cyclophosphamide and isophosphamide. Cyclophosphamide is one of the most widely used anti-cancer agents in the world and is administered in combination with a number of other drugs to treat a wide variety of hematologic and solid tumors. However, several features of the cyclophosphamide detract from its clinical efficacy. For example, the drug requires metabolic activation in the liver to produce metabolites that are toxic to cancer cells. The drug is specifically toxic to the urinary bladder, and it also displays the bone marrow toxicity typical of the alkylating agent class of anti-cancer drugs. Cyclophosphamide is a potent suppressor of the immune system at the doses used to treat cancer, thus decreasing the infection-fighting ability of patients already debilitated by their disease. Finally, repeated use of cyclophosphamide frequently results in the development of resistance to the drug in a patient""s cancer cells, thus rendering the drug ineffective.
Phosphoramidate derivatives have long been known in the literature and are well documented as alkylating reagents. Some of them have been found to be useful in the treatment of cancer (for a review see, DeVita, xe2x80x9cPrinciples of Cancer Therapyxe2x80x9d, pages 765-788 in Petersdorf, et al. Principles of Internal Medicine, 10th ed. McGraw-Hill, NY., 1983). Cyclophospharnide analogs are also well known to the literature and have been extensively derivatized (Cyclophosphamide, Merck Index, 11th Edition pages 429-430, U.S. Pat. No. 5,190,929). However, there have been relatively few references to bis-(N,Nxe2x80x2-bis-(2-chloroethyl)amino) phosphoramidates (DE19524515, U.S. Pat. No. 5,306,727, WO9306120, DE3835772, GB2207674, DE3239858, EP072531). U.S. Pat. No. 5,556,942 discloses the compound 
in which Z is bromine, and R is hydrogen, or R is chlorine as a synthetic reaction intermediate.
In a first aspect, this invention is phosphoramidate compounds of the formula: 
where:
X is a halogen atom;
Q is O, S, or NH; and
R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or is Rxe2x80x2COxe2x80x94, Rxe2x80x2NHCOxe2x80x94, Rxe2x80x2SO2xe2x80x94, or Rxe2x80x2NHSO2xe2x80x94 where Rxe2x80x2 is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or R-Q together is chlorine,
and the pharmaceutically acceptable salts thereof.
In a second aspect, this invention is pharmaceutical compositions comprising a therapeutically effective amount of a compound of the first aspect of the invention and at least one pharmaceutically acceptable carrier.
In a third aspect, this invention is methods of treatment of disease states in a mammal where administration of an anti-mitotic agent is beneficial, such as tumors and cancer, the method comprising to the mammal a therapeutically effective amount of a compound of the first aspect of the invention, in particular as a composition of the second aspect of the invention.
In a fourth aspect, this invention is processes for the preparation of compounds of the first aspect of the invention.
Terms used herein are based upon their recognized meanings and should be clearly understood by those skilled in the art.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d includes fluorine, chlorine, bromine, and iodine. Preferred halogens are chlorine and bromine.
The term xe2x80x9calkylxe2x80x9d, as in xe2x80x9calkylxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d, means a C1-C20 monovalent hydrocarbyl group which may be linear, branched, or cyclic. The term xe2x80x9clower alkylxe2x80x9d, as in xe2x80x9clower alkylxe2x80x9d, xe2x80x9chalo-lower alkylxe2x80x9d, xe2x80x9caryl(lower)alkylxe2x80x9d, or xe2x80x9cheteroaryl(lower)alkylxe2x80x9d, means a fully saturated monovalent hydrocarbon group having from 1 to 10 carbon atoms containing only carbon and hydrogen atoms, and which may be cyclic, branched or straight chain. This term is exemplified by groups such as methyl, ethyl, isopropyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclopropylmethyl, cyclohexyl or cyclohexylmethyl. In the context of the present invention, a lower alkyl of 1 to 6 carbon atoms is preferred.
The term xe2x80x9csubstituted alkyl or substituted lower alkylxe2x80x9d is an alkyl or lower alkyl, respectively, which is mono-, di-, or trisubstituted with a group selected from aryl, R1-substituted aryl, heteroaryl, nitro, cyano, halogen, xe2x80x94OR1, xe2x80x94SR1, xe2x80x94C(O)R1, xe2x80x94OC(O)R1, xe2x80x94C(O)OR1, xe2x80x94NR12, xe2x80x94SO2OR1, xe2x80x94OSO2R1, xe2x80x94SO2NR12, xe2x80x94NR1SO2R1, xe2x80x94CONR12, or xe2x80x94NR1C(O)R1, where each R1 is, independently, hydrogen, lower alkyl, R2-substituted lower alkyl, aryl, R2-substituted aryl, heteroaryl, heteroaryl(lower)alkyl, R2-substituted aryl(lower)alkyl, or aryl(lower)alkyl and each R2 is, independently, hydroxy, halogen, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower alkyl or amino. Substituted alkyls or substituted lower alkyls which are substituted with one to three of the substituents selected from the group consisting of cyano, halo, lower alkyloxy, thio, nitro, amino, and hydroxy are particularly preferred.
The term xe2x80x9chalo-lower alkylxe2x80x9d means a lower alkyl substituted with one to three halo groups, such as xe2x80x94CF3, xe2x80x94CH2CF3 and xe2x80x94CH2CCl3.
The term xe2x80x9caryl(lower)alkylxe2x80x9d means a lower alkyl which is substituted with an aryl. A xe2x80x9csubstituted aryl(lower)alkylxe2x80x9d means an aryl(lower)alkyl having one to three substituents on the aryl portion or the alkyl portion of the radical, or both.
The term xe2x80x9cheteroaryl(lower)alkylxe2x80x9d means a lower alkyl which is substituted with a heteroaryl. A xe2x80x9csubstituted heteroaryl(lower)arylxe2x80x9d means a heteroaryl(lower)alkyl having one to three substituents on the heteroaryl portion or the alkyl portion of the radical, or both.
The term xe2x80x9clower alkyloxyxe2x80x9d means an xe2x80x94OR3 radical, where R3 is a lower alkyl.
The term xe2x80x9carylxe2x80x9d, as in xe2x80x9carylxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, and xe2x80x9caryl(lower)alkylxe2x80x9d, means a monovalent group derived from an aromatic hydrocarbon containing 6 to 20 ring carbon atoms, having a single ring (e.g., phenyl), or two or more condensed rings, preferably 2 to 3 condensed rings (e.g., naphthyl), or two or more aromatic rings, preferably 2 to 3 aromatic rings, which are linked by a single bond (e.g., biphenyl). The aryl is preferably C6-C16 and even more preferably, C6 to C14.
The term xe2x80x9csubstituted arylxe2x80x9d means an aryl substituted with one to three substituents selected from alkyl, substituted alkyl, halogen, cyano, nitro, xe2x80x94SR1, xe2x80x94OR1, xe2x80x94C(O)R1, xe2x80x94OC(O)R1, xe2x80x94SO2OR1, xe2x80x94OSO2R1, xe2x80x94SO2NR12, xe2x80x94NR1SO2R1, xe2x80x94C(O)OR1, xe2x80x94NR12, xe2x80x94CONR12, or xe2x80x94NR1C(O)R1, where each R1 is, independently, hydrogen, lower alkyl, R2-substituted lower alkyl, aryl, R2-substituted aryl, heteroaryl, heteroary(lower)alkyl, aryl(lower)alkyl, or R2-substituted aryl(lower)alkyl and each R2 is, independently hydroxy, halo, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower alkyl or amino. In addition, any two adjacent substituents on the aryl may optionally together form a lower alkylenedioxy. Particularly preferred substituents on the substituted aryl include hydroxy, halo, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower akyl, halo-lower alkyl, or amino.
The term xe2x80x9cheteroarylxe2x80x9d, as in heteroaryl and heteroaryl(lower)alkyl, means a radical derived from an aromatic hydrocarbon containing 5 to 14 ring atoms, 1 to 5 of which are hetero atoms chosen, independently, from N, O, or S, and includes monocyclic, condensed heterocyclic, and condensed carbocyclic and heterocyclic aromatic rings (e.g., thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl, isobenzofuranyl, purinyl, isoquinolyl, pteridinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, quinolyl, etc.).
The term xe2x80x9csubstituted heteroarylxe2x80x9d means a heteroaryl having from one to three substituents selected from alkyl, R1-substituted alkyl, halo, cyano, nitro, xe2x80x94SR1, xe2x80x94OR1, xe2x80x94C(O)R1, xe2x80x94OC(O)R1, xe2x80x94SO2OR1, xe2x80x94OSO2R1, xe2x80x94SO2NR12, xe2x80x94NR1SO2R1, xe2x80x94C(O)OR1, xe2x80x94NR12, xe2x80x94CONR12, or xe2x80x94NR1C(O)R1, where each R1 is independently hydrogen, lower alkyl, R2-substituted lower alkyl, aryl, R2-substituted aryl, heteroaryl, heteroaryl(lower)alkyl, aryl(lower)alkyl, or R2-substituted aryl(lower)alkyl and each R2 is, independently, hydroxy, halo, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower alkyl, or amino. In addition, any two adjacent substituents on the heteroaryl may optionally together form a lower alkylenedioxy. Particularly preferred substituents on the substituted heteroaryl include hydroxy, halo, lower alkyloxy, cyano, thio, nitro, lower alkyl, halo-lower alkyl, halo-lower alkyl, or amino.
The term xe2x80x9cdiseasexe2x80x9d, in the context of the present invention, is intended to include tumors, in particular cancer, and other diseases which may benefit from an anti-mitotic agent including but not limited to benign hyperplasia and infections by pathogenic agents such as fungal and parasitic infections.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d means salts which may be formed when acidic groups, more specifically, acidic protons present are capable of reacting with inorganic or organic bases. Acidic protons are, for example, present in the groups xe2x80x94OR1, xe2x80x94SO2OR1, or xe2x80x94C(O)OR1. Typically the parent compound is treated with an excess of an alkaline reagent, such as hydroxide, carbonate or alkoxide, containing an appropriate cation. Cations such as Na+, K+, Ca2+ and NH4+ are examples of cations present in pharmaceutically acceptable salts. The Na+ salts are especially useful. Acceptable inorganic bases, therefore, include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Salts may also be prepared using organic bases, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, ethanolamine, and tromethamine. If the compounds of the invention contain a basic group, an acid addition salt may be prepared. Examples of basic groups are xe2x80x94NR12 groups. Acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts), nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid, p-toluenesulfonic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, lactic acid, o-(4-hydroxy-benzoyl)benzoic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2.]oct-2-ene-1-carboxylic acid, glucoheptonic acid, gluconic acid, 4,4xe2x80x2-methylenebis(3-hydroxy-2-naphthoic)acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, glucuronic acid, glutamic acid, 3-hydroxy-2-naphthoic acid, stearic acid, muconic acid and the like. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d also include inner salts or zwitterions. Zwitterions would be formed if a compound of Formula I contains both acidic protons and basic groups. xe2x80x9cInner saltsxe2x80x9d or xe2x80x9czwitterionsxe2x80x9d can be formed by transferring a proton from the carboxyl group onto the lone pair of electrons of the nitrogen atom in the amino group.
The term xe2x80x9cstereoisomersxe2x80x9d are compounds that have the same sequence of covalent bonds and differ in the relative disposition of their atoms in space.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to the amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
The term xe2x80x9canti-mitoticxe2x80x9d refers to a drug or agent that interferes with the division of the nucleus of a eukaryotic cell.
The term xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease in a mammal includes:
(1) preventing the disease from occurring in a mammal which may be predisposed to the disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting its development, or
(3) relieving symptoms of the disease, i.e., causing regression of the disease.
Certain compounds of the invention may contain one or more chiral centers. In such cases, all stereoisomers also fall within the scope of this invention. The compounds within the scope of the invention therefore are understood to include the individually isolated stereoisomers as well as mixtures of such stereoisomers.
Within the compounds of the first embodiment of the invention, certain compounds (including as pharmaceutically acceptable salts of the compounds) are preferred.
These preferences include compounds where:
(1) X is chlorine or bromine, especially chlorine;
(2) Q is O;
(3) R is Rxe2x80x2COxe2x80x94, Rxe2x80x2NHCOxe2x80x94, Rxe2x80x2SO2xe2x80x94, or Rxe2x80x2NHSO2xe2x80x94, where Rxe2x80x2 is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, especially where R is acetyl, benzoyl, benzenesulfonyl, para-bromobenzenesulfonyl, para-nitrobenzenesulfonyl, para-toluenesulfonyl, or methanesulfonyl; or
(3xe2x80x2) R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; especially where R is hydrogen, methyl, or benzyl.
Within the compounds of the invention, compounds in which a given preference is met are preferred over those in which the preference is not met; and compounds having a greater number of preferences met are preferred over compounds in which a smaller number of preferences is met.
Particularly preferred compounds are those in which X is chlorine, Q is O, and R is hydrogen, benzyl, acetyl, benzoyl, benzenesulfonyl, para-bromobenzenesulfonyl, para-nitrobenzenesulfonyl, para-toluenesulfonyl, or methanesulfonyl, or R-Q together is chlorine; and the compounds 2-hydroxyethyl-N,N,Nxe2x80x2,Nxe2x80x2-tetrakis(2-chloroethyl)phosphorodiamidate and 2-chloroethyl-N,N,Nxe2x80x2,Nxe2x80x2-tetrakis(2-chloroethyl)phosphorodiamidate are particularly preferred.
The compounds of Formula I possess anti-tumor activities or are capable of being modified to have anti-tumor activities. The 2-haloethyl, more specifically, the 2-chloroethyl portion of the molecule in these compounds can act directly as an alkylator of DNA or can be transformed into an aziridinyl. The aziridinyl form is a highly active form of the molecule and is the proposed mechanism for the nitrogen mustard class of compounds. Therefore, the compounds are effective in treating tumors and other diseases which may benefit from an anti-mitotic agent, such as benign hyperplasia and infections by pathogenic agents. These compounds do not have to be metabolically activated in the liver to acquire anti-tumor activity and, therefore, do not have the same toxicity profile as cyclophosphamides.
The compounds of the invention may be administered in a therapeutically effective amount by any of the usual and acceptable routes to the patient being treated. Routes of administration include, but are not limited to, administration by injection, including intravenous, intraperitoneal, intramuscular, and subcutaneous injection, by transmucosal or transdermal delivery, through topical application, nasal spray, suppository and the like or may be administered orally.
The therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the patient, the potency of the compound used and other factors. It is usually in the range of approximately 1 milligram per Kg (mg/Kg) body weight per day to 1,000 mg/Kg body weight per day, preferably in the range of approximately 1 to 100 mg/Kg/day.
In general, compounds of the invention will be administered as pharmaceutical compositions which can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, or any other appropriate composition and are comprised of, in general, a compound of formula I in combination with at least one pharmaceutically acceptable carrier. Acceptable carriers are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula I. Such excipient may be any solid, liquid or semisolid.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.) Preferred liquid carriers, particularly suitable for injection solutions, include water, saline, aqueous dextrose and glycols.
The amount of a compound of Formula I in the composition may vary widely depending upon the type of composition, size of a unit dosage, kind of excipients and other factors known to those skill in the art of pharmaceutical sciences. In general, the final composition will comprise from 1% w/w to 99% w/w, more preferably, 10% w/w to 90% w/w of the compound, most preferably 25% w/w to 75% w/w with the remainder being the excipient or excipients.
The pharmaceutical compositions are prepared following the conventional techniques of pharmacy.
Pharmaceutical compositions comprising a therapeutically effective amount of a compound of the first aspect of this invention (including as a pharmaceutically acceptable salt form of the compound), and at least one pharmaceutically acceptable carrier are likewise an embodiment of this invention.
The present invention further contemplates administration of a pharmaceutical composition of one or more compounds of the first aspect of this invention to be used alone or in combination with other pharmacological agents. A preferred embodiment of the present invention includes combination therapy where a pharmaceutical composition of one or more compounds of the first aspect of this invention are used in combination with other pharmacologically active agents selected from the group consisting of antibiotics, antineoplastic agents, tumoricidal agents, tumoristatic agents and the like. Such use of combination therapy may be readily practiced by those skilled in the art following generally accepted standards of medical care and based upon generally accepted clinical principles.
The present invention also contemplates methods of treatment for tumors, in particular cancer, in a mammal, comprising administering a therapeutically effective amount of a compound of the first aspect of this invention (including as a pharmaceutically acceptable salt form of the compound to a mammal in need thereof. 
The compounds of Formula I may be prepared according to the reaction scheme depicted above and described below:
Compound B can be prepared by reacting phosphorus oxychloride with compound A, bis(2-haloethyl)amine halide. The reaction mixture is reacted in an inert solvent. Inert solvents may be aromatic hydrocarbons. A base is added to the reaction mixture, more preferably, an organic base such as organic amine, most preferably, triethylamine is added to the reaction mixture, and the reaction mixture is then stirred for an extended period of time at 0-50xc2x0 C. The mixture, frequently a suspension, is heated to 0-100xc2x0 C. and stirred for an extended period of time. The mixture is then cooled, treated with an adsorbent, for example, charcoal, stirred at room temperature, and filtered. The solvent is then removed to produce a compound B.
Compound B is subsequently reacted with a compound C. The reaction is carried out in a polar solvent. The reaction mixture is stirred/agitated and then cooled. Alkali alkoxide is added to the mixture, which is then slowly warmed to 0-50xc2x0 C. and stirred for an extended period of time. A solution of hydrogen halide, for example, HCl, in water is introduced into the reaction mixture. The organic fraction is collected, and the aqueous fraction is extracted with a water-immiscible aprotic polar solvent (2xc3x974 L). Water-immiscible aprotic polar solvents include dichloromethane, chloroform, and the like. The combined organic fractions are washed , and the solvents are removed under reduced pressure. The resulting crude product of the reaction, a compound of Formula (I), is then washed and purified by conventional means.
More specifically, compound 2 (see synthetic scheme 2, below) can be prepared by reacting phosphorous oxychloride with 1 namely, bis(2-haloethyl)amine hydrochloride. The reaction mixture in a solvent such as toluene, benzene, xylene and the like is stirred/agitated at a moderate rate (to provide a clear solution) and triethylamine is added to the reaction mixture over a period of 5-30 minutes. The reaction mixture is then stirred for an extended period of time at room temperature. To this mixture is added an additional amount of bis(2-haloethyl)amine hydrochloride and triethylamine. The resulting suspension is heated to the reflux temperature of the solvent and stirred for 16-24 hours. The mixture is then cooled to room temperature and treated with charcoal, stirred at room temperature for 2 hours and then vacuum filtered through a pad of Celite. The solvent is then removed under reduced pressure (30 mm Hg, final bath temperature at 50xc2x0 C.) on a rotary evaporator to produce a compound 2.
Compound 2 thus prepared is then reacted with a compound 3. The reaction is carried out in a solvent such as tetrahydrofuran, dioxane, tert-butylmethylether and the like. The reaction mixture is stirred/agitated at a moderate rate (to provide a clear red solution) and the mixture is cooled to 0xc2x0 C. using an ice/water bath. To this cooled solution is added potassium tert-butoxide (362 g, 3.22 moles) over 20 minutes. The reaction mixture is then slowly warmed to room temperature and stirred for an extended period of time (16-24 hours). A solution of hydrogen chloride in water is introduced into the reaction mixture at this stage. The organic fraction is collected and the aqueous fraction is extracted with ethyl acetate (2xc3x974 L). The combined organic fractions are washed with saturated aqueous sodium chloride solution (1xc3x974 L) and the solvents are removed under reduced pressure (30 mm Hg vacuum, final bath temperature at 50xc2x0 C.) on a rotary evaporator. The resulting crude product of the reaction, a compound of Formula (I), is then washed and purified by conventional means.
In this synthesis, reactants such as phosphorus oxychloride, compounds 1 and 3 are all commercially available from sources such as Aldrich, Fluka and Alfa.
In the synthesis of certain compounds of Formula I, protective groups may be introduced and finally removed. Suitable protective groups for amino, hydroxyl, carboxyl groups are described in Greene, et al. xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d Second Edition, John Wiley and Sons, New York, 1991. Some derivatives require esterification of alcohols, which may be achieved by methods well known in the art (see, for example, Larock, xe2x80x9cComprehensive Organic Transformationsxe2x80x9d, VCH Publishers, New York, 1989).
Accordingly, the process for preparing a compound of Formula I comprises one or more of the following steps:
(a) reacting a compound of Formula (2) 
with a compound of Formula(3) 
;or
(b) elaborating substituents of a compound of Formula I in a manner known per se; or
(c) converting a compound of Formula I where R is hydrogen and Q is oxygen into a compound of Formula I where R-Q together is an ester group; or
(d) reacting the free base of a compound of Formula I with an acid to give a pharmaceutically acceptable addition salt; or
(e) reacting an acid addition salt of a compound of Formula I with a base to form the corresponding free base; or
(f) converting a salt of a compound of Formula I to another pharmaceutically acceptable salt of a compound of Formula I; or
(g) resolving a racemic mixture of any proportions of a compound of Formula I to yield a stereoisomer thereof.